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Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination

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    Small-Molecule Thioesters as SARS-CoV-2 Main Protease Inhibitors: Enzyme Inhibition, Structure–Activity Relationships, Antiviral Activity, and X-ray Structure Determination
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    • Thanigaimalai Pillaiyar*
      Thanigaimalai Pillaiyar
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Cluster of Excellence iFIT (EXC 2180) “Image-Guided & Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany
      *Email: [email protected]
      More by Thanigaimalai Pillaiyar
      Orcidhttps://orcid.org/0000-0001-5575-8896
    • Philipp Flury
      Philipp Flury
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Cluster of Excellence iFIT (EXC 2180) “Image-Guided & Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany
      More by Philipp Flury
    • Nadine Krüger
      Nadine Krüger
      Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, Germany
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    • Haixia Su
      Haixia Su
      CAS Key Laboratory of Receptor Research, and Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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    • Laura Schäkel
      Laura Schäkel
      PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn D-53121, Germany
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    • Elany Barbosa Da Silva
      Elany Barbosa Da Silva
      Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States
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      Orcidhttps://orcid.org/0000-0002-1926-3500
    • Olga Eppler
      Olga Eppler
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Cluster of Excellence iFIT (EXC 2180) “Image-Guided & Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany
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    • Thales Kronenberger
      Thales Kronenberger
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Cluster of Excellence iFIT (EXC 2180) “Image-Guided & Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany
      More by Thales Kronenberger
    • Tianqing Nie
      Tianqing Nie
      CAS Key Laboratory of Receptor Research, and Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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    • Stephanie Luedtke
      Stephanie Luedtke
      Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States
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    • Cheila Rocha
      Cheila Rocha
      Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, Germany
      More by Cheila Rocha
    • Katharina Sylvester
      Katharina Sylvester
      PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn D-53121, Germany
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    • Marvin R.I. Petry
      Marvin R.I. Petry
      PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn D-53121, Germany
      More by Marvin R.I. Petry
    • James H. McKerrow
      James H. McKerrow
      Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States
      More by James H. McKerrow
      Orcidhttps://orcid.org/0000-0002-5152-4627
    • Antti Poso
      Antti Poso
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Cluster of Excellence iFIT (EXC 2180) “Image-Guided & Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany
      School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio 70211, Finland
      More by Antti Poso
      Orcidhttps://orcid.org/0000-0003-4196-4204
    • Stefan Pöhlmann
      Stefan Pöhlmann
      Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, Göttingen 37077, Germany
      Faculty of Biology and Psychology, University Göttingen,Göttingen 37073, Germany
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    • Michael Gütschow
      Michael Gütschow
      PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn D-53121, Germany
      More by Michael Gütschow
      Orcidhttps://orcid.org/0000-0002-9376-7897
    • Anthony J. O’Donoghue
      Anthony J. O’Donoghue
      Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California 92093, United States
      More by Anthony J. O’Donoghue
    • Yechun Xu*
      Yechun Xu
      CAS Key Laboratory of Receptor Research, and Stake Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
      *Email: [email protected]
      More by Yechun Xu
      Orcidhttps://orcid.org/0000-0002-1581-6155
    • Christa E. Müller
      Christa E. Müller
      PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, Bonn D-53121, Germany
      More by Christa E. Müller
      Orcidhttps://orcid.org/0000-0002-0013-6624
    • Stefan A. Laufer
      Stefan A. Laufer
      Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany. Cluster of Excellence iFIT (EXC 2180) “Image-Guided & Functionally Instructed Tumor Therapies”, University of Tübingen, Tübingen 72076, Germany
      More by Stefan A. Laufer
      Orcidhttps://orcid.org/0000-0001-6952-1486
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 13, 9376–9395
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    https://doi.org/10.1021/acs.jmedchem.2c00636
    Published June 16, 2022
    Copyright © 2022 American Chemical Society
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    Abstract

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    The main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target in coronaviruses because of its crucial involvement in viral replication and transcription. Here, we report on the design, synthesis, and structure–activity relationships of novel small-molecule thioesters as SARS-CoV-2 Mpro inhibitors. Compounds 3w and 3x exhibited excellent SARS-CoV-2 Mpro inhibition with kinac/Ki of 58,700 M–1 s–1 (Ki = 0.0141 μM) and 27,200 M–1 s–1 (Ki = 0.0332 μM), respectively. In Calu-3 and Vero76 cells, compounds 3h, 3i, 3l, 3r, 3v, 3w, and 3x displayed antiviral activity in the nanomolar range without host cell toxicity. Co-crystallization of 3w and 3af with SARS-CoV-2 Mpro was accomplished, and the X-ray structures showed covalent binding with the catalytic Cys145 residue of the protease. The potent SARS-CoV-2 Mpro inhibitors also inhibited the Mpro of other beta-coronaviruses, including SARS-CoV-1 and MERS-CoV, indicating that they might be useful to treat a broader range of coronaviral infections.

    Copyright © 2022 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00636.

    • Inhibition of proteases (Figures S1–S7); cell vitality and antiviral activity of inhibitors (Figures S8–S12); broad-spectrum Mpro inhibitory activities of thioesters (Figures S13–S14); potential binding mode of compounds (Figure S15); GSH stability data for 3an (Figure S16); selected hits from the virtual screening (Table S1); crystallography data collection and refinement statistics (Table S2); synthesis of LN5535 (Scheme S1); 1H and 13C NMR spectra and the HPLC traces of selected compounds; Preliminary Full wwPDB X-ray Structure Validation Report for3w and 3af (PDF)

    • Molecular formula strings and the associated biological data (CSV)

    • 3CLpro-3af (PDB code 7X6J) (PDB)

    • 3CLpro-3w (PDB code 7X6K) (PDB)

    • CCDC file for 3w (PDF)

    • CCDC file for 3af (PDF)

    Accession Codes

    The authors will release the atomic coordinates (3w, PDB ID: 7X6K) (A) and (3af, PDBID: 7X6J) upon article publication.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2022, 65, 13, 9376–9395
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    https://doi.org/10.1021/acs.jmedchem.2c00636
    Published June 16, 2022
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